PROJECT SUMMARY By the year 2050, the number of individuals in the United States over the age of 65 is expected to increase to over 80 million, comprising 20% of the population. The incidence of most common cancers increases with age and fatigue is one of the most prevalent and debilitating symptoms in patients with cancer, affecting 70-100% of patients, with the highest prevalence in elderly patients. The prevalence is even higher in patients receiving chemotherapy and/or radiation therapy. In spite of the significance of the burden, there are currently no FDA- approved treatments for cancer-related fatigue. In addition to fatigue, sexual dysfunction and decreased lean body mass are also highly prevalent in older men with cancer and contribute to decreased physical function and poor quality of life (QOL). This phenotype is commonly encountered in non-cancer older men with low serum testosterone levels. Testosterone deficiency is highly prevalent (50-90%) in older men with cancer. Clinical trials of testosterone replacement therapy in non-cancer older men have shown an improvement in well-being, QOL, sexual function and body composition in men randomized to testosterone compared with placebo. However, the efficacy of testosterone replacement therapy on cancer-related fatigue has not been studied. The overall goal of this proposal is to evaluate the efficacy of physiologic testosterone replacement therapy in improving fatigue and other outcomes such as sexual function, QOL, body composition, muscle strength and physical function in a double-blind, randomized, placebo-controlled trial in older men with incurable solid tumors who report fatigue and have low testosterone levels. We propose a large, 6-month trial in which we will compare the efficacy of physiologic testosterone replacement with a transdermal testosterone gel (the most convenient and widely used form of testosterone replacement) versus placebo gel in men age 60 and older with cancer who report fatigue and have testosterone deficiency. The following outcomes will be measured: 1) fatigue scores, 2) sexual function, well-being, mood and quality of life and caregiver burden, and 3) body composition, muscle strength and physical function. We will also perform qualitative surveys to explore lived experiences of the trial participants. With the growing recognition of the importance of symptom control in the lives of patients with cancer, including those undergoing cancer therapies, the proposed trial is highly relevant given that it is likely to have a significant impact on symptom management and quality of life in older men with cancer. If testosterone therapy is found to be efficacious in alleviating these symptoms, the clinicians will have available to them a therapeutic option that is inexpensive, convenient to use and relatively safe.